Herrera et al.
classical conditions to obtain triflates from ketones.32 The
instability of 14 did not allow its isolation.
filtered through Celite, which was washed with EtOH (100 mL).
The solvent was removed in vacuo, and the residue was purified
by distillation or recrystallization after column chromatography
(eluent, EtOAc/hexanes ) 5/95).
5-Methyl-2-(4-methoxyphenyl)-1,3-oxazole (12g): white needles
(from MeOH); yield 93%; mp 60-61 °C; IR (KBr) ν 1616, 1501,
1254, 1173, 837 cm-1; 1H NMR (CD3OD) δ 2.39 (d, J ) 1.1 Hz,
3H, CH3), 3.85 (s, 3H, CH3O), 6.85 (q, J ) 1.1 Hz, 1H, H4), 7.02
(m, 2H, Ar-H), 7.88 (m, 2H, Ar-H); 13C NMR (CD3OD) δ 10.77
(CH3-C5), 55.9 (CH3O), 121.0, 124.1 (aromatic), 128.6 (C5), 150.3
(C4), 162.3 (C2), 162.9 (aromatic); MS (EI) m/z (% B) 189 (M+•,
100), 174 (M - CH3, 16), 146 (M - CH3CO, 44); Anal. Calcd.
for C11H11NO2: C, 69.83; H, 5.86; N, 7.40. Found: C, 69.72; H,
5.73; N, 7.33.
In summary, we reported a new and simple procedure to
prepare 2,4,5-trisubstituted 1,3-oxazoles. The easy desulfuration
with Raney nickel of the methylthio group at the C4 position
allows the synthesis of 2,5-disubstituted 1,3-oxazoles. The
oxidation of the methylthio group with m-CPBA permits the
preparation of 4-methylsulfonyl derivatives. A NMR study of
the reaction at low temperature revealed species that were
incorporated in a proposed mechanism for the reaction.
Experimental Section
General Procedure for the Synthesis of 2-Substituted 5-Methyl-
4-(methylthio)-1,3-oxazoles, 8. To a solution of 1-(methylthio)-
acetone 7 (2.00 g, 19.2 mmol) in dry CH2Cl2 (25 mL) was added
triflic anhydride (5.34 g, 19.2 mmol) in CH2Cl2 (20 mL) dropwise
at 0 °C. The mixture was stirred for 1 h at this temperature, and
then a solution of the corresponding nitrile (9.6 mmol) in CH2Cl2
(20 mL) was added. The mixture was stirred and allowed to stand
at 0 °C for 3 days. The progress of the reaction was monitored by
TLC. The reaction mixture was hydrolyzed by the careful addition
of saturated NaHCO3. The organic layer was separated, washed
with brine, and dried over MgSO4. The solvent was evaporated in
vacuo, and the residue was purified by distillation or recrystalli-
zation after column chromatography (eluent, EtOAc/hexanes )
5/95).
General Procedure for the Synthesis of 2-Substituted 5-Methyl-
4-(methylsulfonyl)-1,3-oxazoles, 13. To a solution of the corre-
sponding oxazole 8 (3 mmol) in 25 mL dry CH2Cl2 was added
dropwise a solution of m-CPBA (7 mmol, 12 mmol for 8c) in 25
mL of dry CH2Cl2. The reaction mixture was stirred at room
temperature for 12 h. The reaction was hydrolyzed by the addition
of 20 mL of 5% sodium thiosulfate. The organic layer was washed
with saturated NaHCO3 and brine and dried over MgSO4. The
solvent was removed in vacuo, and the residue was purified by
distillation or recrystallization after column chromatography (eluent,
EtOAc/hexanes ) 5/95).
2-Phenyl-5-methyl-4-(methylsulfonyl)-1,3-oxazole (13d): white
crystals (from MeOH); yield 93%; mp 130-131 °C; IR (KBr) ν
1
1595, 1313, 1153, 785, 714 cm-1; H NMR δ 2.71 (s, 3H, CH3),
2-Phenyl-5-methyl-4-(methylthio)-1,3-oxazole (8d): yellow oil;
yield 92%; bp 125 °C/0.4 Torr (kugelrohr); IR (film) ν 2924, 1591,
1487, 1109, 714 cm-1; 1H NMR δ 2.35 (s, 3H, CH3), 2.37 (s, 3H,
CH3S), 7.35 (m, 3H, Ar-H), 7.95 (m, 2H, Ar-H); 13C NMR δ
10.3 (CH3-C5), 17.7 (CH3S), 125.8, 127.0, 128.41, 128.9 (aro-
3.22 (s, 3H, CH3SO2), 7.48 (m, 3H, Ar-H), 8.03 (m, 2H, Ar-H);
13C NMR δ 11.4 (CH3-C5), 42.7 (CH3SO2), 125.8, 126.6, 128.8,
131.2 (aromatic), 135.7 (C5), 153.0 (C4), 160.2 (C2); MS (EI) m/z
(% B) 237 (M+•, 19), 105 (C6H5CO+, 100), 77 (C6H5+, 39); Anal.
Calcd. for C11H11NO3S: C, 55.68; H, 4.67; N, 5.90; S, 13.51.
Found: C, 55.55; H, 4.56; N, 5.80; S, 13.43.
matic), 130.4 (C5), 148.9 (C4), 159.7 (C2); MS (EI) m/z (% B)
+
205 (M+•, 43), 172 (M - SH, 38), 105 (C6H5CO+, 100), 77 (C6H5
,
Low-Temperature NMR Spectra. To a solution of 0.0104 g
(0.10 mmol) of 7 in 0.8 mL of CDCl3 at 5 °C contained in a NMR
tube was added 0.0282 g (0.10 mmol) of Tf2O. The tube was sealed
with a septum, introduced in the spectrometer, and spun. The spectra
were recorded at 30 min intervals. After the appropriate time,
benzonitrile (0.0103 g, 0.10 mmol) was added, and the spectra were
recorded at the same time intervals.
54); Anal. Calcd for C11H11NOS: C, 64.36; H, 5.40; N, 6.82; S,
15.62. Found: C, 64.13; H, 5.22; N, 6.69; S, 15.49.
Bisoxazolyl derivatives 10 and 11 were prepared using the
general procedure from methylthioacetone 7 and nitriles 8k and
8l.
5-Methyl-2-{4-[5-methyl-4-(methylthio)-1,3-oxazol-2-yl]phen-
yl}-4-(methylthio)-1,3-oxazole (11): pale yellow solid (from
EtOH); yield 80%, mp 142-143 °C; this compound presents in
solution an intense greenish fluorescence; IR (KBr) ν 1589, 1418,
Acknowledgment. We thank the DGESIC (Spain, Grant
BQU2002-00406) for financial support and the CAIs of the
UCM (Madrid, Spain) for determining spectra and CHN
analyses.
1063, 719 cm-1 1H NMR δ 2.47 (s, 6H, 2CH3), 2.48 (s, 6H,
;
2CH3S), 8.17 (s, 4H, Ar-H); 13C NMR δ 10.6 (CH3-C5), 18.0
(CH3S), 126.5, 128.37 (aromatic), 131.0 (C5), 149.8 (C4), 159.4
(C2); MS (EI) m/z (% B) 332 (M+•, 100), 317 (M - CH3, 5), 299
(M - SH, 50), 232 ([C5H6NOS]C6H5CO+, 14); Anal. Calcd. for
C16H16N2O2S2: C, 57.81; H, 4.85; N, 8.43; S, 19.29. Found: C,
57.70; H, 4.69; N, 8.32; S, 19.14.
Supporting Information Available: General experimental
methods and characterization data of compounds 8a-c, 8e-l, 10,
12d, 13c, 13f, and 13j; 1H, 13C, and DEPT (135) NMR spectra of
compounds 8a-l, 10, 11, 12d, 12g, 13c, 13d, 13f, and 13j; 2D
NMR (HMQC and HMBC) spectra of compound 8d; fluorescence
spectra of 11; 1H, 13C, and 2D NMR spectra of the reaction mixture
at low temperature (5 °C); and 1H and 13C chemical shifts of
intermediates 14, 15, and 16. This material is available free of
General Procedure for the Synthesis of 2-Substituted 5-Methyl-
1,3-oxazoles, 12. Compound 8 (3 mmol) was dissolved in EtOH
and added to a suspension of recently prepared Raney nickel32 in
20 mL EtOH. The reaction mixture was refluxed for 48 h and then
(32) Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R.
Vogel’s Textbook of Practical Organic Chemistry; Longman Scientific &
Technical: Essex, 1989.
JO052619V
3032 J. Org. Chem., Vol. 71, No. 8, 2006